Compounds for use in disorders associated with mast cell or basophil acitvity

ABSTRACT

The present invention relates to the use certain compounds for the treatment, prevention or alleviation of a disorder or disease of a subject, which disorder or disease is responsive to modulation of the mast cell or basophil activity of such a subject.

The present invention relates to the use certain compounds for thetreatment, prevention or alleviation of a disorder or disease of asubject, which disorder or disease is responsive to modulation of themast cell or basophil activity of such a subject.

BACKGROUND ART

Mast cells and basophils play a key role in the pathogenesis of severalimmunological and inflammatory diseases, not only by producinginflammatory and fibrogenic mediators, but also by directly andindirectly secreting various cytokines and chemokines.

Due to the frequency and severity of many of these diseases, there is acontinued strong interest in the development of a more selective andeffective therapy with fewer side effects for the treatment of thediseases.

A number of chloride channel blockers are described in the internationalpatent applications WO 97/45400, WO 98/47879, WO 00/20378, and WO00/24707 (all NeuroSearch A/S).

SUMMARY OF THE INVENTION

In its first aspect, the invention relates to the use of a compound ofthe general formula IA-(X)_(p)—(Y)_(q)-(Z)_(r)-B   (I)

or a pharmaceutically acceptable salt or a prodrug thereof for themanufacture of a medicament for the treatment, prevention or alleviationof a disorder or disease of a subject, which disorder or disease isresponsive to modulation of the mast cell or basophil activity of such asubject. Other objects of the invention will be apparent to the personskilled in the art from the following detailed description and examples.

DETAILED DISCLOSURE OF THE INVENTION

We have now found that these compounds can be used for treating adisorder or disease of a living animal body, which is responsive tomodulation of the mast cell or basophil activity of such a living animalbody.

Thus, in its first aspect, the invention provides the use of a compoundof the general formula IA-(X)_(p)—(Y)_(q)-(Z)_(r)-B   (I)

wherein

A represents a first ring structure selected from aryl, or heteroaryl;

which first ring structure is optionally substituted with one or moresubstituents independently selected from the group consisting of:

halogen, hydroxy, amino, oxy, cyano, nitro, trifluoromethyl,trifluoromethoxy, trifluorothiomethoxy

alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, alkoxy,

aryl, arylalkyl, aryloxy, arylcarboxy, heteroaryl, —N(R²)-aryl,

a 5- or 6-membered monocyclic heterocyclic group,

—CO₂R¹, —COR¹, -alkyl-CO₂R¹, -alkyl-COR¹,

—N(R²)₂, -alkyl-N(R²)₂, —CO₂N(R¹)₂, —NHCOR¹, —CON(R¹)₂, —NHSO₂R¹,—CONHSO₂R¹, —SO₂N(R¹)₂, and —SO₂OR¹;

wherein each of the alkyl, alkoxy, and cycloalkyl is optionallysubstituted with one or more substitutents independently selected fromthe group consisting of:

halogen, hydroxy, amino, cyano, nitro, trifluoromethyl,trifluoromethoxy, trifluorothiomethoxy alkyl, cycloalkyl,cycloalkylalkyl, alkenyl, and alkynyl;

each of the aryl, heteroaryl, and 5- or 6-membered monocyclicheterocyclic group is optionally substituted with one or more one ormore substitutents independently selected from the group consisting of:

halogen, hydroxy, amino, cyano, nitro, trifluoromethyl,trifluoromethoxy, trifluorothiomethoxy alkyl, cycloalkyl,cycloalkylalkyl, alkenyl, alkynyl, alkoxy,

aryl, heteroaryl, —CO₂R³, —COR³,

—N(R⁴)₂, -alkyl-N(R⁴)₂, —CON(R³)₂, —NHCOR³, —CON(R³)₂, —NHSO₂R³,—SO₂N(R³)₂, and —SO₂OR³;

each of R¹ and R³ independently is selected from the group consistingof:

hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, aryl,arylalkyl, heteroaryl, and

a 5-8 membered ring optionally containing double bonds and optionallycontaining one or two heteroatoms, which heteroatoms can be substitutedwith alkyl or acyl;

or (R¹)₂ or (R³)₂ independently together with the heteroatom to which itis connected represents a 5-8 membered ring optionally containing doublebonds and optionally containing another heteroatom, which heteroatom canbe substituted with alkyl or acyl;

each of R² and R⁴ independently is hydrogen or alkyl;

B represents a second ring structure

selected from aryl, or heteroaryl;

which second ring structure is substituted with one or more acidicfunctional group having a pKa value below 8, or a group which isconvertible in vivo to such a group, or a bioisostere thereof;

and which second ring structure is furthermore optionally substitutedwith one or more substituents independently selected from the groupconsisting of:

halogen, hydroxy, amino, oxy, cyano, nitro, trifluoromethyl,trifluoromethoxy, trifluorothiomethoxy

alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, alkoxy,

aryl, arylalkyl, aryloxy, arylcarboxy, heteroaryl, —N(R⁶)-aryl,

a 5- or 6-membered monocyclic heterocyclic group,

—CO₂R⁵, —COR⁵, -alkyl-CO₂R⁵, -alkyl-COR⁵,

—N(R⁶)₂, -alkyl-N(R⁶)₂, —CON(R⁵)₂, —NHCOR⁵, —CON(R⁵)₂, —NHSO₂R⁵,—CONHSO₂R⁵, —SO₂N(R⁵)₂, and —SO₂OR⁵;

wherein each of the alkyl, alkoxy, and cycloalkyl is optionallysubstituted with one or more substitutents independently selected fromthe group consisting of:

halogen, hydroxy, amino, cyano, nitro, trifluoromethyl,trifluoromethoxy, trifluorothiomethoxy alkyl, cycloalkyl,cycloalkylalkyl, alkenyl, and alkynyl;

each of the aryl, heteroaryl, and 5- or 6-membered monocyclicheterocyclic group is optionally substituted with one or more one ormore substitutents independently selected from the group consisting of:

halogen, hydroxy, amino, cyano, nitro, trifluoromethyl,trifluoromethoxy, trifluorothiomethoxy alkyl, cycloalkyl,cycloalkylalkyl, alkenyl, alkynyl, alkoxy,

aryl, heteroaryl, —CO₂R⁷, —COR⁷,

—N(R⁸)₂, -alkyl-N(R⁸)₂, —CO₂N(R⁷)₂, —NHCOR⁷, —CON(R⁷)₂, —NHSO₂R⁷,—SO₂N(R⁷)₂, and —SO₂OR⁷;

each of R⁵ and R⁷ independently is selected from the group consistingof:

hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, aryl,arylalkyl, heteroaryl, and

a 5-8 membered ring optionally containing double bonds and optionallycontaining one or two heteroatoms, which heteroatoms can be substitutedby alkyl or acyl;

or (R⁵)₂ or (R⁷)₂ independently together with the heteroatom to which itis connected represents a 5-8 membered ring optionally containing doublebonds and optionally containing another heteroatom, which heteroatom canbe substituted by alkyl or acyl;

each of R⁶ and R⁸ independently is hydrogen or alkyl;

X, Y, and Z are independently selected from the group consisting of:

—CO—, —CS—, —SO₂—, —C(═NR⁹)—, —NR¹⁰—, —(CH₂)_(s)—, —O—,

—CH₂—NH—, —SO₂—NH—, —CH═CH—, —C≡C—, and —N═CH—;

wherein s is 1, 2, or 3;

R⁹ is hydrogen, alkyl, or cyano;

R¹⁰ is hydrogen or alkyl;

p, q, and r independently are 0 or 1;

the sum p+q+r is 1, 2, or 3;

or —(X)_(p)—(Y)_(q)-(Z)_(r)- represents

wherein

Q¹ and Q² independently represent O or S;

R¹¹ and R¹² independently are hydrogen or alkyl;

or a pharmaceutically acceptable salt or a prodrug thereof for themanufacture of a medicament for the treatment, prevention or alleviationof a disorder or disease of a subject, which disorder or disease isresponsive to modulation of the mast cell or basophil activity of such asubject.

In a further aspect, the invention provides a method of treatment,prevention or alleviation of a disorder or disease of a subject, whichdisorder or disease is responsive to modulation of the mast cell orbasophil activity of such a subject, which method comprisesadministering to said subject a therapeutically effective amount of acompound of general formula I or a pharmaceutically acceptable salt or aprodrug thereof.

In one embodiment, the acidic functional group having a pKa below 8, ora group which is convertible in vivo to such a group is selected fromthe group consisting of:

—COOH, —CH₂CO₂R¹³, —CON(R¹³)₂, tetrazolyl, methyltetrazolyl,3-oxo-1,2-dihydro-1,2,4-triazolyl, 2-oxo-3H-1,3,4-oxadiazolyl,3-oxo-1,2-dihydro-1,2,4-triazolyl, 4-hydro-1,2,4-triazolyl, —NHSO₂R¹³,—CO₂R¹³, —CO₂N(R¹³)₂, —SO₂OR¹³, —SO₂N(R¹³)₂, —CONHOH, —CONHNH₂,—CONHSO₂R¹³, —CONHSO₂OR³, —PO(OR¹³)₂, and —SO₂)R¹³;

wherein each of R¹³ independently is selected from the group consistingof:

hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, aryl,aralkyl, and heteroaryl;

or R¹³ comprises a 5-8 membered ring optionally containing double bondsand optionally containing one or two heteroatoms, which heteroatoms canbe substituted by alkyl or acyl;

or (R¹³)₂ together with the heteroatom to which it is connectedrepresents a 5-8 membered ring optionally containing double bonds andoptionally containing another heteroatom, which heteroatoms can besubstituted by alkyl or acyl.

In a second embodiment, the bioisostere of the acidic functional groupis two neighbouring fluoro.

In a third embodiment, the second ring structure is substituted with anacidic functional group having a pKa below 8, or a group which isconvertible in vivo to such a group, or a bioisostere thereof, in theposition nearest or second nearest to the position attached to—(X)_(p)—(Y)_(q)-(Z)_(r)-.

In a further embodiment, the acidic functional group having a pKa below8, or a group which is convertible in vivo to such a group is selectedfrom the group consisting of:

—COOH, —CH₂CO₂R¹³, —CON(R¹³)₂, tetrazolyl, methyltetrazolyl, —NHSO₂R¹³,—CO₂R¹³, —CO₂N(R¹³)₂, —SO₂N(R¹³)₂, —CONHSO₂R¹³, —PO(OR¹³)₂, and—SO₂OR¹³;

wherein R¹³ is as defined above.

In a still further embodiment, the first ring structure is optionallysubstituted with one or more substituents independently selected fromthe group consisting of:

trifluoromethyl, halogen, alkyl, alkoxy, nitro, —COR¹, —COOH, —CH₂CO₂R¹,—CON(R¹)₂, —NHSO₂R¹, —NHCOR¹, —CO₂R¹, —CO₂N(R¹)₂, —SO₂N(R¹)₂,—CONHSO₂R¹, —SO₂OR¹, and aryl;

wherein the aryl optionally is substituted with one or more substituentsselected from the group:

—NO₂, —NHCOR³, —CO₂R³, —CON(R³)₂, —NHSO₂R³, and —SO₂N(R³)₂;

wherein R¹ and R³ are defined as above.

In a further embodiment, the second ring structure is substituted withone or more acidic functional group having a pKa value below 8, or agroup which is convertible in vivo to such a group, or a bioisosterethereof;

and which second ring structure is furthermore optionally substitutedwith one or more substituents independently selected from the groupconsisting of:

alkyl, nitro, amino, alkylamino, CO₂R⁹, CF₃, alkyl, halogen, hydroxy,alkoxy, —NHCOR⁵, —N(R⁵)₂, —CON(R⁵)₂, and aryl,

wherein the aryl is optionally substituted with one or more substituentsindependently selected from the group consisting of:

—NO₂, —CON(R⁷)₂, —NHCOR⁷, —SO₂N(R⁷)₂, and —CO₂R⁷;

wherein R⁵ and R⁷ are defined as above.

In a still further embodiment, X is —NR⁹—, Y is —CO— or —CS—, Z is—NR¹⁰—, p is 1, q is 1 and r is 1; wherein R¹⁰ is defined as above.

In a further embodiment, Y is —CO— or —CS—, Z is —NR¹⁰—, p is 0, q is 1,and r is 1.

In a still further embodiment, X is —CH₂—, Y is —CH₂—, Z is —NR¹⁰—, p is1, q is 1 and r is 1.

In a further embodiment, X is —NR¹⁰—, Y is —SO₂—, Z is —NR¹⁰—, p is 1, qis 1 and r is 1.

In a still further embodiment, X is —CH₂—NH—, Y is —CO— or —CS—, Z is—NR¹⁰—, p is 1, q is 1 and r is 1.

In a further embodiment, X is —O—, Y is —CO—, Z is —NR¹⁰—, p is 1, q is1 and r is 1.

In a still further embodiment, X is —SO₂—NH—, Y is —CO—, Z is —NH—, p is1, q is 1 and r is 1.

In a further embodiment, X is —NR¹⁰—, Y is —(CH₂)_(s)—, Z is —NR¹⁰—, pis 1, q is 1 and r is 1; wherein s is defined as above.

In a special embodiment, R¹⁰ is hydrogen.

In a further embodiment, s is 2.

In a still further embodiment, —(X)_(p)—(Y)_(q)-(Z)_(r)- represents

In a further embodiment, the first ring structure is phenyl, naphthyl,indanyl, or pyridyl.

In a still further embodiment, the second ring structure is phenyl,naphthyl, indanyl or pyridyl.

In a special embodiment, the first ring structure is phenyl, the secondring structure is phenyl, and —(X)_(p)—(Y)_(q)-(Z)_(r)- represents—NH—CO—NH—.

In a further special embodiment, the first ring structure is phenyl, thesecond ring structure is phenyl, —(X)_(p)—(Y)_(q)-(Z)_(r)- represents—NH—CO—NH—, and the acidic functional group having a pKa below 8 is—COOH or tetrazolyl, and the bioisostere of the acidic functional grouphaving a pKa below 8 is two neighbouring fluoro.

In a still further special embodiment, A represents 3-biphenylyl,3-chlorophenyl, 3-nitrophenyl, 3-trifluoromethylphenyl,3,5-bis(trifluoromethyl)phenyl, 3,4-dichlorophenyl,4-chloro-3-trifluoromethylphenyl, or 4-fluoro-3-trifluoromethylphenyl.

In a further special embodiment, B represents2-(1-H-tetrazol-5-yl)phenyl, 2-carboxy-5-chlorophenyl,2-carboxy-5-fluorophenyl, 2-carboxy-5-nitrophenyl,5-chloro-2-(1-H-tetrazol-5-yl )phenyl, 2,3,4-trifluorophenyl,2,3-difluorophenyl, 2,4-dibromo-6-(1-H-tetrazol-5-yl)phenyl, or4-bromo-2-(1-H-tetrazol-5-yl)phenyl.

In a special embodiment, the compound of general formula I is selectedfrom:

3-Trifluoromethylphenyl-N′-2-carboxyphenyl urea

N-3-Trifluoromethylphenyl-N′-3-carboxyphenyl urea;

N-(2-Methoxy-5-chlorophenyl)-N′-3-carboxyphenyl urea;

N-3-Trifluoromethylphenyl-N′-(2-carboxy-5-nitrophenyl) urea;

N-3-Trifluoromethylphenyl-N′-(2-carboxy-4-methylphenyl) urea;

N-3-Trifluoromethylphenyl-N′-(4-bromo-2-carboxyphenyl) urea;

N-3-Trifluoromethylphenyl-N′-3-carbamoylphenyl urea;

N-3-Trifluoromethylphenyl-N′-3-sulfamoylphenyl urea;

N-3-Trifluoromethylphenyl-N′-(5-chloro-2-phenylsulfonamidocarbonylphenyl)urea;

N-3-Trifluoromethylphenyl-N′-2-methylsulfonamidocarbonylphenyl urea;

N-3-Trifluoromethylphenyl-N′-(6-methyl-2-carboxyphenyl) urea;

N-3-Trifluoromethylphenyl-N′-(3-methyl-2-carboxyphenyl) urea;

N-3-Trifluoromethylphenyl-N′-(4-hydroxy-2-carboxyphenyl) urea;

N-4-Nitrophenyl-N′-2-carboxyphenyl urea;

N-3-Trifluoromethylphenyl-N′-2-carboxymethylphenyl urea;

N-3-Trifluoromethylphenyl-N′-2-sulfophenyl urea;

N-3-Trifluoromethylphenyl-N′-2-carboxyphenyl thiourea;

N-3-Trifluoromethylphenyl-N′-(2-carboxy-5-trifluoromethylphenyl) urea;

N-3-Trifluoromethylphenyl-N′-(4,5-dimethoxy-2-carboxyphenyl) urea;

N-3-Carboxyphenyl-N′-(2-hydroxy-5-chlorophenyl) urea;

N-3-Carbamoylphenyl-N′-(2-hydroxy-5-chlorophenyl) urea;

N-3-Trifluoromethylphenyl-N′-(2-hydroxy-4-nitro-5-carboxyphenyl) urea;

N-3-Trifluoromethylphenyl-N′-(4-carboxy-5-chloro-2-hydroxyphenyl) urea;

N-3-Trifluoromethylphenyl-N′-(2-amino-5-chlorophenyl) urea;

N-3-Trifluoromethylphenyl-N′-(5-chloro-2-methanesulfonylaminophenyl)urea;

N-3-Trifluoromethylphenyl-N′-2-carboxyphenyl urea isopropyl ester;

N-3-Trifluoromethylphenyl-N′-2-carboxyphenyl urea methyl ester;

N-3-Trifluoromethylphenyl-N′-2-hydrazinocarbonylphenyl urea;

N-3-Trifluoromethylphenyl-N′-2-hydroxylaminocarbonylphenyl urea;

2-(3′-Trifluoromethylbenzylcarboxamido)benzoic acid;

N-3-Trifluoromethylphenyl-N′-4-carboxyphenyl urea;

N-3-Trifluoromethylphenyl-N′-(2-carboxy-4-nitrophenyl) urea;

N-3-Trifluoromethylphenyl-N′-2-carboxynapht-3-yl urea;

N-3-Trifluoromethylphenyl-N′-(4-methoxy-2-carboxyphenyl) urea;

N-3-Methoxyphenyl-N′-2-carboxyphenyl urea;

N-4-Bromophenyl-N′-2-carboxyphenyl urea;

N-3-Nitrophenyl-N′-2-carboxyphenyl urea;

N-2-Methoxyphenyl-N′-2-carboxyphenyl urea;

N-4-Methoxyphenyl-N′-2-carboxyphenyl urea;

N-1-Naphthyl-N′-2-carboxyphenyl urea;

N-2-Trifluoromethyl phenyl-N′-2-carboxyphenyl urea;

N-4-Methylphenylsulfonyl-N′-2-carboxyphenyl urea;

N-3-Trifluoromethylphenyl-N′-(2-ethyloxycarbonylphenyl)-1,2-diaminoethane;

N-(3-Trifluoromethyl)phenyl-N′-(2-carboxy)phenylsulfamide;

N-3-Trifluoromethylbenzyl-N′-2-carboxyphenyl urea;

N-(3-Trifluoromethyl-4-phenylphenyl)-N′-2-carboxyphenyl urea;

2-(3′-Trifluoromethylphenyloxycarbonylamino)benzoic acid;

N-3-Trifluoromethylphenyl-N′-(5-chloro-2-aminophenyl) urea;

N-3-Trifluoromethylphenyl-N′-[4-nitro-2-(1-H-tetrazol-5-yl)phenyl] urea;

N-3-Trifluoromethylphenyl-N′-[4-(2-naphthyl)-2-(1-H-tetrazol-5-yl)phenyl]urea;

N-3-Trifluoromethylphenyl-N′-[4-(3-pyridyl)-2-(1-H-tetrazol-5-yl)phenyl]urea;

N-3-Trifluoromethylphenyl-N′-[4-(1-naphthyl)-2-(1-H-tetrazol-5-yl)phenyl]urea;

N-3-Trifluoromethylphenyl-N′-[4-(4-trifluoromethylphenyl)-2-(1-H-tetrazol-5-yl)phenyl]urea;

N-3-Trifluoromethylphenyl-N′-[4-(3-furyl)-2-(1-H-tetrazol-5-yl)phenyl]urea;

N-3-Trifluoromethylphenyl-N′-[4-(3-thienyl)-2-(1-H-tetrazol-5-yl)phenyl]urea;

N-3-Trifluoromethylphenyl-N′-[4-(3-nitrophenyl)-2-(1-H-tetrazol-5-yl)phenyl]urea;

N-3-Trifluoromethylphenyl-N′-[4-(4-ethoxycarbonylphenyl)-2-(1-H-tetrazol-5-yl)phenyl]urea;

N-3-Trifluoromethylphenyl-N′-[4-(4-dimethylaminocarbonylphenyl)-2-(1-H-tetrazol-5-yl)phenyl]urea;

N-3-Trifluoromethylphenyl-N′-[4-(4-aminocarbonylphenyl)-2-(1-H-tetrazol-5-yl)phenyl]urea;

N-3-Trifluoromethylphenyl-N′-2-(4-hydroxy-1,2,4-triazol-3-yl)phenylurea;

N-3-Trifluoromethylphenyl-N′-2-(3-oxo-1,2-dihydro-1,2,4-triazol-1-yl)phenylurea;

N-3-Trifluoromethylphenyl-N′-2-(2-oxo-3H-1,3,4-oxadiazol-5-yl)phenylurea;

N-3-Trifluoromethylphenyl-N′-[5-phenyl-2-(3-oxo-1,2-dihydro-1,2,4-triazol-1-yl)phenyl]urea;

N-3-Trifluoromethylphenyl-N′-[4-amino-2-(1-H-tetrazol-5-yl)phenyl] urea;

N-3-Trifluoromethylphenyl-N′-[4-acetylamino-2-(1-H-tetrazol-5-yl)phenyl]urea;

N-3-Trifluoromethylphenyl-N′-[4-benzoylamino-2-(1-H-tetrazol-5-yl)phenyl]urea;

N-3-Trifluoromethylphenyl-N′-[4-(4-carboxyphenyl)-2-(1-H-tetrazol-5-yl)phenyl]urea;

N-3-Trifluoromethylphenyl-N′-[4-(4-aminocarbonylphenyl)-2-(1-H-tetrazol-5-yl)phenyl]urea;

N-4-Biphenylyl-N′-2-(1-H-tetrazol-5-yl)phenyl urea;

N-3-Biphenylyl-N′-2-(1-H-tetrazol-5-yl)phenyl urea;

N-5-Indanyl-N′-2-(1-H-tetrazol-5-yl)phenyl urea;

N-3-Bromophenyl-N′-[4-bromo-2-(1-H-tetrazol-5-yl)phenyl] urea;

N-3-Acetylphenyl-N′-2-(1-H-tetrazol-5-yl)phenyl urea;

N-3-Biphenylyl-N′-[4-bromo-2-(1-H-tetrazol-5-yl)phenyl] urea;

N-3-(3-Pyridyl)phenyl-N′-[4-bromo-2-(1-H-tetrazol-5-yl)phenyl] urea;

N-3-Trifluoromethylphenyl-N′-[4-bromo-2-(1-H-tetrazol-5-yl)phenyl urea];

N-3-Trifluoromethylphenyl-N′-2-(1-H-tetrazol-5-yl)phenyl urea;

N-3-Trifluoromethylphenyl-N′-2-(1-H-tetrazol-5-yl)phenyl thiourea;

N-3-Trifluoromethylphenyl-N′-[4-phenyl-2-(1-H-tetrazol-5-yl)phenyl]urea;

N-4-Trifluoromethylphenyl-N′-2-(1-H-tetrazol-5-yl)phenyl urea;

N-3-Chlorophenyl-N′-2-(1-H-tetrazol-5-yl)phenyl urea;

N-Phenyl-N′-2-(1-H-tetrazol-5-yl)phenyl urea;

N-3-Bromophenyl-N′-[4-bromo-2-(1-H-tetrazol-5-yl)phenyl] urea;

3-[4-Bromo-2-(1-H-tetrazol-5-yl)-phenylamino]-4-(3-trifluoromethyl-phenylamino)-3-cyclobuten-1,2-dione;

3-(3-Bromo-phenylamino)-4-[4-bromo-(1-H-tetrazol-5-yl)-phenylamino]-3-cyclobuten-1,2-dione;

3-(3-Bromo-phenylamino)-4-[4′-(N,N-dimethylsulfonamide)-2-(1-H-tetrazol-5-yl)-biphenylamino]-3-cyclobuten-1,2-dione;

3-(3-Bromo-phenylamino)-4-[2-(1-H-tetrazol-5-yl)-biphenylamino]-3-cyclobuten-1,2-dione;

N-Phenyl-N′-(2-carboxyphenyl) urea;

N-3-Trifluoromethylphenyl-N′-(2-carboxyphenyl)-N′-methyl urea;

N-3-Trifluoromethylphenyl-N′-(4-bromo-2-carboxyphenyl) urea;

N-3-Trifluoromethylphenyl-N′-(2-carboxy-4-chlorophenyl) urea;

N-3-Trifluoromethylphenyl-N′-(2-carboxy-4-fluorophenyl) urea;

N-3-Trifluoromethylphenyl-N′-(5-bromo-2-carboxyphenyl) urea;

N-3-Trifluoromethylphenyl-N′-(2-carboxy-5-chlorophenyl) urea;

N-3-Bromophenyl-N′-[2-(1-H-tetrazol-5-yl)-4-biphenyl] urea;

N-3-Trifluoromethylphenyl-N′-[4′-(N,N-dimethylsulfamoyl)-2-(1-H-tetrazol-5-yl)-4-biphenyl]urea;

N-3-Bromophenyl-N′-[4′-(N,N-dimethylsulfamoyl)-2-(1-H-tetrazol-5-yl)-4-biphenyl]urea;

N-3-Bromophenyl-N′-[4′-(N,N-dimethylcarbamoyl)-2-(1-H-tetrazol-5-yl)-4-biphenyl]urea;

N-3-Trifluoromethylphenyl-N′-[4-amino-2-(1-H-tetrazol-5-yl)phenyl] urea;

N-3-Trifluoromethylphenyl-N′-[4-acetylamino-2-(1-H-tetrazol-5-yl)phenyl]urea;

N-3-Trifluoromethylphenyl-N′-[4′-carbamoyl-2-(1-H-tetrazol-5-yl)-4-biphenyl] urea;

N-3-Trifluoromethylphenyl-N′-[4′-(N,N-dimethylcarbamoyl)-2-(1-H-tetrazol-5-yl)-4-biphenyl]urea;

N-3-Trifluoromethylphenyl-N′-[4′-carboxy-2-(1-H-tetrazol-5-yl)-4-biphenyl]urea;

1-(3-Trifluoromethylphenyl)-3-(2-carboxyphenyl)-2-imidazolidone;

N-3-Trifluoromethylphenyl-N′-[4-(4-benzoylcarbonylphenyl)-2-(1-H-tetrazol-5-yl)phenyl] urea;

N-4-Biphenylyl-N′-2-(1-H-tetrazol-5-yl)phenyl urea;

N-3-Bromophenyl-N′-[3′-nitro-2-(1-H-tetrazol-5-yl)biphenyl] urea;

N-3-Bromophenyl-N′-[4′-(sulfoamido-N-methylpiperaziniumchloride)-2-(1-H-tetrazol-5-yl)-4-biphenyl] urea;

N-3-Bromophenyl-N′-[4′-(carbamoyl-N-methylpiperazine)-2-(1-H-tetrazol-5-yl)-4-biphenyl]urea;

N-3,5-Dichlorophenyl-N′-[4-bromo-2-(1-H-tetrazol-5-yl)phenyl] urea;

N-4-Trifluoromethylphenyl-N′-[4-bromo-2-(1-H-tetrazol-5-yl)phenyl] urea;

N-4-Bromophenyl-N -[4-bromo-2-(1-H-tetrazol-5-yl)phenyl] urea;

N-3-Methoxyphenyl-N′-[4-bromo-2-(1-H-tetrazol-5-yl)phenyl] urea;

N-3-Chlorophenyl)-N′-[4-bromo-2-(1-H-tetrazol-5-yl)phenyl] urea;

N-3-Methylphenyl-N′-[4-bromo-2-(1-H-tetrazol-5-yl)phenyl] urea;

N-3,4-Dichlorophenyl-N′-[4-bromo-2-(1-H-tetrazol-5-yl)phenyl] urea;

N-2-Naphthyl-N′-[4-bromo-2-(1-H-tetrazol-5-yl)phenyl] urea;

N-(4-Methyl-3-nitrophenyl)-N′-[4-bromo-2-(1-H-tetrazol-5-yl)phenyl]urea;

N-(2-Chloro-4-trifluoromethylphenyl)-N′-[4-bromo-2-(1-H-tetrazol-5-yl)phenyl]urea;

N-3,5-Di(trifluoromethyl)phenyl-N′-[4-bromo-2-(1-H-tetrazol-5-yl)phenyl]urea;

N-3,5-Dimethylphenyl-N-[4-bromo-2-(1-H-tetrazol-5-yl)phenyl] urea;

N-4-Ethoxyphenyl-N′-[4-bromo-2-(1-H-tetrazol-5-yl)phenyl] urea;

N-4-Methoxyphenyl-N′-[4-bromo-2-(1-H-tetrazol-5-yl)phenyl] urea;

N-2-Trifluoromethylphenyl-N′-[4-bromo-2-(1-H-tetrazol-5-yl)phenyl] urea;

N-2-Bromophenyl-N′-[4-bromo-2-(1-H-tetrazol-5-yl)phenyl] urea;

N-2-Chlorophenyl-N′-[4-bromo-2-(1-H-tetrazol-5-yl)phenyl] urea;

N-2-Fluorophenyl-N′-[4-bromo-2-(1-H-tetrazol-5-yl)phenyl] urea;

N-(4-Chloro-3-trifluoromethylphenyl)-N′-[4-bromo-2-(-H-tetrazol-5-yl)phenyl]urea;

N-3-Bromophenyl-N-2,3-difluorophenyl urea;

N-2-Methylphenyl-N′-[4-bromo-2-(1-H-tetrazol-5-yl)phenyl] urea;

N-2-Ethylphenyl-N′-[4-bromo-2-(1-H-tetrazol-5-yl)phenyl] urea;

N-4-Methylphenyl-N′-[4-bromo-2-(1-H-tetrazol-5-yl)phenyl] urea;

N-2-Nitrophenyl-N′-[4-bromo-2-(1-H-tetrazol-5-yl)phenyl] urea;

N-3-Fluorophenyl-N-[4-bromo-2-(1-H-tetrazol-yl)phenyl] urea;

N-4-(2-Propyl)phenyl-N′-[4-bromo-2-(1-H-tetrazol-5yl)phenyl] urea;

N-3-Nitrophenyl-N′-[4-bromo-2-(1-H-tetrazol-5-yl)phenyl] urea;

N-3-Acetylphenyl-N′-[4-bromo-2-(1-H-tetrazol-5-yl)phenyl] urea;

N-4-Nitrophenyl-N′-[4-bromo-2-(1-H-tetrazol-5-yl)phenyl] urea;

N-3-Trifluoromethylphenyl-N′-2-carboxyphenyl urea;

N-Phenyl-N′-2-carboxyphenyl urea;

N-3-Trifluoromethylphenyl-N′-2-carboxyphenyl-N-methyl urea;

N-3-Trifluoromethylphenyl-N′-[4′-(N-phenylcarbamoyl)-2-(1-H-tetrazol-5-yl)-4-biphenyl]urea;

N-(2-Indan)-N -2-(1-H-tetrazol-5-yl)phenyl urea;

N-(4-Biphenyl)-N′-2-(1-H-tetrazol-5-yl)phenyl urea;

N-(3-Biphenyl)-N′-2-(1-H-tetrazol-5-yl)phenyl urea;

N-(3-Acetylphenyl)-N′-2-(1-H-tetrazol-5-yl)phenyl urea;

N-3-Trifluoromethylphenyl-N′-[2-(1-methyltetrazol-5-yl)-4-biphenyl]urea;

N-(3-Biphenyl)-N-[4-bromo-2-(1-H-tetrazol-5-yl)phenyl] urea;

N-3-(3-Pyridyl)phenyl-N′-[4-bromo-2-(1-H-tetrazol-5-yl)phenyl] ureahydrochloride;

N-3-Bromophenyl-N′-[4-bromo-2-(1-H-tetrazol-5-yl)phenyl] urea;

1-(3-Trifluoromethylphenyl)-3-(2-carboxyphenyl)-2-imidazolidone;

N-(4-Biphenylyl)-N′-2-(1-H-tetrazol-5-yl)phenyl urea;

N-(3-Biphenylyl)-N′-2-(1-H-tetrazol-5-yl)phenyl urea;

N-(5-Indanyl)-N′-2-(1-H-tetrazol-5-yl)phenyl urea;

N-(2-Chloro-5-trifluoromethylphenyl)-N′-[4-bromo-2-(1-H-tetrazol-5-yl)phenyl]urea;

N-4-Bromophenyl-N′-(2-carboxy-5-chlorophenyl) urea;

N-4-Trifluoromethylphenyl-N′-(2-carboxy-5-chlorophenyl) urea;

N-3-Bromophenyl-N′-(2-carboxy-5-chlorophenyl) urea;

N-3-Nitrophenyl-N′-(2-carboxy-5-chlorophenyl) urea;

N-3-Methoxyphenyl-N′-(2-carboxy-5-chlorophenyl) urea;

N-(4-Chloro-3-trifluoromethylphenyl)-N′-(2-carboxy-5-chlorophenyl) urea;

N-3-Fluorophenyl-N′-(2-carboxy-5-chlorophenyl) urea;

N-3-Fluorophenyl-N′-(2-carboxy-5-fluorophenyl) urea;

N-3-Trifluoromethylphenyl-N′-(2-carboxy-4,5-difluorophenyl) urea;

N-3,5-Bis(trifluoromethyl)phenyl)-N′-(2-carboxy-5-chlorophenyl) urea;

N-3-Trifluoromethylphenyl-N′-(2-carboxy-5-nitrophenyl) urea;

N-3,4-Dichlorophenyl-N′-[5-methyl-2-(1-H-tetrazol-5-yl)phenyl] urea;

N-3,4-Dichlorophenyl-N′-[5-chloro-2-(1-H-tetrazol-5-yl)phenyl] urea;

N-3-Trifluoromethylphenyl-N′-(3-carboxy-4-chlorophenyl) urea;

N-(3-Chloro-4-hydroxyphenyl)-N′-[4-bromo-2-(1-H-tetrazol-5-yl)phenyl]urea;

N-2,3,4-Trifluorophenyl-N′-[4-bromo-2-(1-H-tetrazol-5-yl)phenyl] urea;

N-3,4-Difluorophenyl-N′-[4-bromo-2-(1-H-tetrazol-5yl)phenyl] urea;

N-3-Chlorophenyl-N′-2,3-difluorophenyl urea;

N-(3-Chloro-4-fluorophenyl)-N′-[4-bromo-2-(1-H-tetrazol-5-yl)phenyl]urea;

N-2,4,5-Trifluorophenyl-N′-[4-bromo-2-(1-H-tetrazol-5-yl)phenyl] urea;

N-3,5-Bis(trifluoromethyl)phenyl)-N′-2-(1-H-tetrazol-5-yl)phenyl urea;

N-3,5-Bis(trifluoromethyl)phenyl)-N′-[2,4-dibromo-6-(1-H-tetrazol-5-yl)phenyl]urea;

N-(4-Fluoro-3-trifluoromethylphenyl)-N′-[4-bromo-2-(1-H-tetrazol-5-yl)phenyl]urea;

N-3,5-Difluorophenyl-N′-[4-bromo-2-(1-H-tetrazol-5-yl)phenyl] urea;

N-3,5-Bis(trifluoromethyl)phenyl-N′-[4′-(N,N-dimethylsulfamoyl)-2-(1-H-tetrazol-5-yl)-(4-biphenyl)]urea;

N-3,5-Dichlorophenyl-N′-[4′-(N,N-dimethylsulfamoyl)-2-(1-H-tetrazol-5-yl)-4-biphenyl]urea;

N-2,3-Difluorophenyl-N′-3-trifluoromethylphenyl urea;

N-2, 3-Difluorophenyl-N′-(4-chloro-3-trifluoromethylphenyl) urea;

N-3,4-Dichlorophenyl-N′-2,3-trifluorophenyl urea;

N-2,3-Difluorophenyl-N′-3-trifluoromethylphenyl thiourea;

N-2,3-Difluorophenyl-N′-2-fluorophenyl urea;

N-2,3-Difluorophenyl-N′-3-methoxyphenyl urea;

N-3,4-Dichlorophenyl-N′-2,3,4-trifluorophenyl urea;

N-(4-Chloro-3-trifluoromethylphenyl)-N′-2,3,4-trifluorophenyl urea;

N-3-Chlorophenyl-N′-(2-hydroxy-4-methylphenyl) urea;

N-2,3-Difluorophenyl-N′-[3′-(pyridin-3-yl)phenyl] urea;

N-3,5-Dichlorophenyl-N′-2,3-difluorophenyl urea;

N-2,3-Difluorophenyl-N′-3-nitrophenyl urea; and

pharmaceutically acceptable salts and prodrugs thereof.

The above compounds and their preparation are described in WO97/45400,WO98/47879, WO00/20378, and WO00/24707.

In one embodiment, the compound of general formula I show an inhibitionof more than 10%, preferably more than 25%, and most preferably morethan 50%, when tested for In vitro inhibition of anti-IgE inducedbasophil histamine release (example 1).

The disorders or diseases to be treated include, but are not limited to,disorders or diseases responsive to modulation of mast cell or basophilproduction or secretion of mediators such as histamine, neutralproteases or tryptases (such as chymotryptases and carboxypeptidases),leukotrienes (such as LTC4, and LTB4), prostaglandins (such as PGD2),TXA2, PAF, and cytokines (such as IL-4 and TNF-α).

In a further embodiment, the disorder or disease that is responsive tomodulation of the mast cell or basophil activity is a disorder ordisease that is responsive to modulation of mast cell or basophilproduction or secretion of histamine.

In a still further embodiment, the disorder or disease that isresponsive to modulation of the mast cell or basophil activity isallergic bronchopulmonary aspergillosis (ABPA), allergic rhinitis,allergic skin disease, allergic skin reaction, drug induced allergicskin reaction, anaphylaxis, asthma, atherosclerosis, atopic dermatitis(AD), bronchial asthma, cancer, chronic obstructive pulmonary disease(COPD), Chrohn's disease, contact dermatitis, dilated cardiomyopathy,fatal asthma, graft rejection, hypersensitivity pneumonitis, ischemichearth disease, pulmonary fibrosis, rheumatoid arthritis, systemicsclerosis, urticaria, or uveoretinitis.

In a special embodiment, the disorder or disease that is responsive tomodulation of the mast cell or basophil activity is allergicbronchopulmonary aspergillosis (ABPA), allergic rhinitis, allergic skindisease, allergic skin reaction, drug induced allergic skin reaction,asthma, bronchial asthma, fatal asthma or chronic obstructive pulmonarydisease (COPD). In a further special embodiment, the disorder or diseaseis asthma, bronchial asthma, fatal asthma or chronic obstructivepulmonary disease (COPD). In a further special embodiment, the disorderor disease is COPD. In a still further special embodiment, the disorderor disease is asthma.

Definition of Substituents

In the context of this invention halogen represents a fluorine, achlorine, a bromine or an iodine atom.

Alkyl means a straight chain or branched chain of one to six carbonatoms, including but not limited to, methyl, ethyl, propyl, isopropyl,butyl, isobutyl, t-butyl, pentyl, and hexyl; methyl, ethyl, propyl andisopropyl are preferred groups.

Alkoxy is O-alkyl, wherein alkyl is as defined above.

Acyl is —CO-alkyl wherein alkyl is as defined above.

Aryl is a carbocyclic aromatic ring system such as phenyl, naphthyl(1-naphthyl or 2-naphthyl), indanyl, and indenyl.

The acidic functional group having a pKa below 8 or a group which isconverted in vivo to such group are groups such as3-hydroxy-4-oxo-pyranyl, 2-hydroxy-4-oxo-pyrimidyl,3,5-dioxo-1,2,4-oxadiazolidinyl, 2,4-dioxo-imidazolidinyl,2,5-dioxo-3-hydroxy-pyrrolyl, 2,5-dioxo-pyrrolidinyl,2,4-dioxo-1,3-thiazolidinyl, 3-hydroxy-isoxazolyl, 5-hydroxy-isoxazolyl,3-hydroxy-isothiazolyl, 3-hydroxy-1,2,5-thiadiazolyl, tetrazolyl,1-methyltetrazolyl, 3-hydroxy-triazolyl, 3-hydroxy-pyrazolyl,2-hydroxy-1,3,4-oxadiazolyl, 3-oxo-1,2-dihydro-1,2,4-triazolyl,2-oxo-3H-1,3,4-oxadiazolyl, 4-hydroxy-1,2,4-triazolyl,2-hydroxy-1,3,4-oxadiazolyl or 2-hydroxy-3,4-dioxo-cyclobutenyl, NH₂,—N(R¹³)₂, —OR³, —CO₂R¹³, —CH₂CO₂R¹³, —CON(R¹³)₂, —NHSO₂R¹³, —SO₂N(R¹³)₂,—SO₂OR¹ ³, —SO₂R¹³, —PO(OR¹³)₂, —PO₃H₂, —PO₃R²H, —PO₂NH₂, —CONHOH,—CONHCN, —CONHSO₂R¹³, —CONHSO₂OR¹³ and —CONHNH₂;

wherein each of R¹³ independently is selected from the group consistingof:

hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, aryl,aralkyl, and heteroaryl;

or R¹³ comprises a 5-8 membered ring optionally containing double bondsand optionally containing one or two heteroatoms, which heteroatoms canbe substituted by alkyl or acyl;

or (R¹³)₂ together with the heteroatom to which it is connectedrepresents a 5-8 membered ring optionally containing double bonds andoptionally containing another heteroatom, which heteroatoms can besubstituted by alkyl or acyl.

A bioisostere of an acidic functional group is a functional group whichhas the same biological properties as an acidic functional group. Oneexample of such a bioisostere is two neighbouring fluoro.

Heteroaryl is a 5- or 6-membered heterocyclic monocyclic group. Such amonocyclic heteroaryl group includes, for example, oxazol-2-yl,oxazol-4-yl, oxazol-5-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl,thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, isothiazol-3-yl,isothiazol-4-yl, isothiazol-5-yl, 1,2,4-oxadiazol-3-yl,1,2,4-oxadiazol-5-yl, 1,2,4-thiadiazol-3-yl, 1,2,4-thiadiazol-5-yl,1,2,5-oxadiazol-3-yl, 1,2,5-oxadiazol-4-yl, 1,2,5-thiadiazol-3-yl,1,2,5-thiadiazol-4-yl, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl,1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-furanyl, 3-furanyl, 2-thienyl,3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl,4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, 2-pyrazinyl,1-pyrazolyl, 3-pyrazolyl, and 4-pyrazolyl.

A 5-8 membered ring optionally containing double bonds and optionallycontaining one or two heteroatoms includes for example pyrrolidine,piperidine, piperazine, morpholine, cyclohexyl, cyclohexen,dihydropyrrole, dihydrofuran, dihydrothiophen, dihydropyridine,dihydropyridazine, dihydropyrimidine, dihydropyrazine, tetrahydropyridine, tetrahydropyridazine, tetrahydropyrimid ine, tetrahydropyrazine,homopiperazine, homopiperidine, azacyclooctane.

The compounds of this invention may exist in unsolvated as well as insolvated forms with pharmaceutically acceptable solvents such as water,ethanol and the like. In general, the solvated forms are consideredequivalent to the unsolvated forms for the purposes of this invention.

Pharmaceutically Acceptable Salts

The chemical compound for use according to the invention may be providedin any form suitable for the intended administration. Suitable formsinclude pharmaceutically (i.e. physiologically) acceptable salts, andpre- or prodrug forms of the chemical compound of the invention.

Examples of pharmaceutically acceptable addition salts include, withoutlimitation, the non-toxic inorganic and organic acid addition salts suchas the hydrochloride derived from hydrochloric acid, the hydrobromidederived from hydrobromic acid, the nitrate derived from nitric acid, theperchlorate derived from perchloric acid, the phosphate derived fromphosphoric acid, the sulphate derived from sulphuric acid, the formatederived from formic acid, the acetate derived from acetic acid, theaconate derived from aconitic acid, the ascorbate derived from ascorbicacid, the benzenesulphonate derived from benzensulphonic acid, thebenzoate derived from benzoic acid, the cinnamate derived from cinnamicacid, the citrate derived from citric acid, the embonate derived fromembonic acid, the enantate derived from enanthic acid, the fumaratederived from fumaric acid, the glutamate derived from glutamic acid, theglycolate derived from glycolic acid, the lactate derived from lacticacid, the maleate derived from maleic acid, the malonate derived frommalonic acid, the mandelate derived from mandelic acid, themethanesulphonate derived from methane sulphonic acid, thenaphthalene-2-sulphonate derived from naphtalene-2-sulphonic acid, thephthalate derived from phthalic acid, the salicylate derived fromsalicylic acid, the sorbate derived from sorbic acid, the stearatederived from stearic acid, the succinate derived from succinic acid, thetartrate derived from tartaric acid, the toluene-p-sulphonate derivedfrom p-toluene sulphonic acid, and the like. Such salts may be formed byprocedures well known and described in the art.

Other acids such as oxalic acid, which may not be consideredpharmaceutically acceptable, may be useful in the preparation of saltsuseful as intermediates in obtaining a chemical compound of theinvention and its pharmaceutically acceptable acid addition salt.

Metal salts of a chemical compound of the invention includes alkalimetal salts, such as the sodium salt of a chemical compound of theinvention containing a carboxy group. In the context of this inventionthe “onium salts” of N-containing compounds are also contemplated aspharmaceutically acceptable salts. Preferred “onium salts” include thealkyl-onium salts, the cycloalkyl-onium salts, and thecycloalkylalkyl-onium salts.

Prodrugs

The substance used according to the invention may be administered assuch or in the form of a suitable prodrug thereof. The term “prodrug”denotes a bioreversible derivative of the drug, the bioreversiblederivative being therapeutically substantially inactive per se but beingable to convert in the body to the active substance by an enzymatic ornon-enzymatic process.

Thus, examples of suitable prodrugs of the substances used according tothe invention include compounds obtained by suitable bioreversiblederivatization of one or more reactive or derivatizable groups of theparent substance to result in a bioreversible derivative. Thederivatization may be performed to obtain a higher bioavailability ofthe active substance, to stabilize an otherwise unstable activesubstance, to increase the lipophilicity of the substance administered,etc.

Examples of types of substances which may advantageously be administeredin the form of prodrugs are carboxylic acids, other acidic groups andamines, which may be rendered more lipophilic by suitable bioreversiblederivatization. As examples of suitable groups may be mentionedbioreversible esters or bioreversible amides. Amino acids are typicalexamples of substances which, in their unmodified form, may have a lowabsorption upon administration. Suitable prodrug derivatives of aminoacids will be one or both of the above-mentioned types of bioreversiblederivatives.

Steric Isomers

The chemical compounds of the present invention may exist in (+) and (−)forms as well as in racemic forms. The racemates of these isomers andthe individual isomers themselves are within the scope of the presentinvention.

Racemic forms can be resolved into the optical antipodes by knownmethods and techniques. One way of separating the diastereomeric saltsis by use of an optically active acid, and liberating the opticallyactive amine compound by treatment with a base. Another method forresolving racemates into the optical antipodes is based uponchromatography on an optical active matrix. Racemic compounds of thepresent invention can thus be resolved into their optical antipodes,e.g., by fractional crystallisation of d- or I- (tartrates, mandelates,or camphorsulphonate) salts for example.

The chemical compounds of the present invention may also be resolved bythe formation of diastereomeric amides by reaction of the chemicalcompounds of the present invention with an optically active activatedcarboxylic acid such as that derived from (+) or (−) phenylalanine, (+)or (−) phenylglycine, (+) or (−) camphanic acid or by the formation ofdiastereomeric carbamates by reaction of the chemical compound of thepresent invention with an optically active chloroformate or the like.

Additional methods for the resolving the optical isomers are known inthe art. Such methods include those described by Jaques J, Collet A, &Wilen S in “Enantiomers, Racemates, and Resolutions”, John Wiley andSons, New York (1981).

Optical active compounds can also be prepared from optical activestarting materials.

Pharmaceutical Compositions

While a chemical compound of the invention for use in therapy may beadministered in the form of the raw chemical compound, it is preferredto introduce the active ingredient, optionally in the form of aphysiologically acceptable salt, in a pharmaceutical compositiontogether with one or more adjuvants, excipients, carriers, buffers,diluents, and/or other customary pharmaceutical auxiliaries.

In a preferred embodiment, the invention provides pharmaceuticalcompositions comprising the chemical compound of the invention, or apharmaceutically acceptable salt or derivative thereof, together withone or more pharmaceutically acceptable carriers therefor, and,optionally, other therapeutic and/or prophylactic ingredients, know andused in the art. The carrier(s) must be “acceptable” in the sense ofbeing compatible with the other ingredients of the formulation and notharmful to the recipient thereof.

Pharmaceutical compositions of the invention may be those suitable fororal, rectal, bronchial, nasal, topical (including buccal andsub-lingual), transdermal, vaginal or parenteral (including cutaneous,subcutaneous, intramuscular, intraperitoneal, intravenous,intraarterial, intracerebral, intraocular injection or infusion)administration, or those in a form suitable for administration byinhalation or insufflation, including powders and liquid aerosoladministration, or by sustained release systems. Suitable examples ofsustained release systems include semipermeable matrices of solidhydrophobic polymers containing the compound of the invention, whichmatrices may be in form of shaped articles, e.g. films or microcapsules.

The chemical compound of the invention, together with a conventionaladjuvant, carrier, or diluent, may thus be placed into the form ofpharmaceutical compositions and unit dosages thereof. Such forms includesolids, and in particular tablets, filled capsules, powder and pelletforms, and liquids, in particular aqueous or non-aqueous solutions,suspensions, emulsions, elixirs, and capsules filled with the same, allfor oral use, suppositories for rectal administration, and sterileinjectable solutions for parenteral use. Such pharmaceuticalcompositions and unit dosage forms thereof may comprise conventionalingredients in conventional proportions, with or without additionalactive compounds or principles, and such unit dosage forms may containany suitable effective amount of the active ingredient commensurate withthe intended daily dosage range to be employed.

The chemical compound of the present invention can be administered in awide variety of oral and parenteral dosage forms. It will be obvious tothose skilled in the art that the following dosage forms may comprise,as the active component, either a chemical compound of the invention ora pharmaceutically acceptable salt of a chemical compound of theinvention.

For preparing pharmaceutical compositions from a chemical compound ofthe present invention, pharmaceutically acceptable carriers can beeither solid or liquid. Solid form preparations include powders,tablets, pills, capsules, cachets, suppositories, and dispersiblegranules. A solid carrier can be one or more substances which may alsoact as diluents, flavouring agents, solubilizers, lubricants, suspendingagents, binders, preservatives, tablet disintegrating agents, or anencapsulating material.

In powders, the carrier is a finely divided solid, which is in a mixturewith the finely divided active component.

In tablets, the active component is mixed with the carrier having thenecessary binding capacity in suitable proportions and compacted in theshape and size desired.

The powders and tablets preferably contain from five or ten to aboutseventy percent of the active compound. Suitable carriers are magnesiumcarbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin,starch, gelatin, tragacanth, methylcellulose, sodiumcarboxymethylcellulose, a low melting wax, cocoa butter, and the like.The term “preparation” is intended to include the formulation of theactive compound with encapsulating material as carrier providing acapsule in which the active component, with or without carriers, issurrounded by a carrier, which is thus in association with it.Similarly, cachets and lozenges are included. Tablets, powders,capsules, pills, cachets, and lozenges can be used as solid formssuitable for oral administration.

For preparing suppositories, a low melting wax, such as a mixture offatty acid glyceride or cocoa butter, is first melted and the activecomponent is dispersed homogeneously therein, as by stirring. The moltenhomogenous mixture is then poured into convenient sized moulds, allowedto cool, and thereby to solidify.

Compositions suitable for vaginal administration may be presented aspessaries, tampons, creams, gels, pastes, foams or sprays containing inaddition to the active ingredient such carriers as are known in the artto be appropriate.

Liquid preparations include solutions, suspensions, and emulsions, forexample, water or water-propylene glycol solutions. For example,parenteral injection liquid preparations can be formulated as solutionsin aqueous polyethylene glycol solution.

The chemical compound according to the present invention may thus beformulated for parenteral administration (e.g. by injection, for examplebolus injection or continuous infusion) and may be presented in unitdose form in ampoules, pre-filled syringes, small volume infusion or inmulti-dose containers with an added preservative. The compositions maytake such forms as suspensions, solutions, or emulsions in oily oraqueous vehicles, and may contain formulation agents such as suspending,stabilising and/or dispersing agents. Alternatively, the activeingredient may be in powder form, obtained by aseptic isolation ofsterile solid or by lyophilization from solution, for constitution witha suitable vehicle, e.g. sterile, pyrogen-free water, before use.

Aqueous solutions suitable for oral use can be prepared by dissolvingthe active component in water and adding suitable colorants, flavours,stabilising and thickening agents, as desired.

Aqueous suspensions suitable for oral use can be made by dispersing thefinely divided active component in water with viscous material, such asnatural or synthetic gums, resins, methylcellulose, sodiumcarboxymethylcellulose, or other well known suspending agents.

Also included are solid form preparations, intended for conversionshortly before use to liquid form preparations for oral administration.Such liquid forms include solutions, suspensions, and emulsions. Inaddition to the active component such preparations may comprisecolorants, flavours, stabilisers, buffers, artificial and naturalsweeteners, dispersants, thickeners, solubilizing agents, and the like.

For topical administration to the epidermis the chemical compound of theinvention may be formulated as ointments, creams or lotions, or as atransdermal patch. Ointments and creams may, for example, be formulatedwith an aqueous or oily base with the addition of suitable thickeningand/or gelling agents. Lotions may be formulated with an aqueous or oilybase and will in general also contain one or more emulsifying agents,stabilising agents, dispersing agents, suspending agents, thickeningagents, or colouring agents.

Compositions suitable for topical administration in the mouth includelozenges comprising the active agent in a flavoured base, usuallysucrose and acacia or tragacanth; pastilles comprising the activeingredient in an inert base such as gelatin and glycerine or sucrose andacacia; and mouthwashes comprising the active ingredient in a suitableliquid carrier.

Solutions or suspensions are applied directly to the nasal cavity byconventional means, for example with a dropper, pipette or spray. Thecompositions may be provided in single or multi-dose form.

Administration to the respiratory tract may also be achieved by means ofan aerosol formulation in which the active ingredient is provided in apressurised pack with a suitable propellant such as a chlorofluorocarbon(CFC) for example dichlorodifluoromethane, trichlorofluoromethane, ordichlorotetrafluoroethane, carbon dioxide, or other suitable gas. Theaerosol may conveniently also contain a surfactant such as lecithin. Thedose of drug may be controlled by provision of a metered valve.

Alternatively the active ingredients may be provided in the form of adry powder, for example a powder mix of the compound in a suitablepowder base such as lactose, starch, starch derivatives such ashydroxypropylmethyl cellulose and polyvinylpyrrolidone (PVP).Conveniently the powder carrier will form a gel in the nasal cavity. Thepowder composition may be presented in unit dose form for example incapsules or cartridges of, e.g., gelatin, or blister packs from whichthe powder may be administered by means of an inhaler.

In compositions intended for administration to the respiratory tract,including intranasal compositions, the compound will generally have asmall particle size for example of the order of 5 microns or less. Sucha particle size may be obtained by means known in the art, for exampleby micronization.

When desired, compositions adapted to give sustained release of theactive ingredient may be employed.

The pharmaceutical preparations are preferably in unit dosage forms. Insuch form, the preparation is subdivided into unit doses containingappropriate quantities of the active component. The unit dosage form canbe a packaged preparation, the package containing discrete quantities ofpreparation, such as packaged tablets, capsules, and powders in vials orampoules. Also, the unit dosage form can be a capsule, tablet, cachet,or lozenge itself, or it can be the appropriate number of any of thesein packaged form.

Tablets or capsules for oral administration and liquids for intravenousadministration and continuous infusion are preferred compositions.

Further details on techniques for formulation and administration may befound in the latest edition of Remington's Pharmaceutical Sciences(Maack Publishing Co., Easton, Pa.).A therapeutically effective doserefers to that amount of active ingredient, which ameliorates thesymptoms or condition. Therapeutic efficacy and toxicity, e.g. ED₅₀ andLD₅₀, may be determined by standard pharmacological procedures in cellcultures or experimental animals. The dose ratio between therapeutic andtoxic effects is the therapeutic index and may be expressed by the ratioLD₅₀/ED₅₀. Pharmaceutical compositions exhibiting large therapeuticindexes are preferred.

The dose administered must of course be carefully adjusted to the age,weight and condition of the individual being treated, as well as theroute of administration, dosage form and regimen, and the resultdesired, and the exact dosage should of course be determined by thepractitioner.

The actual dosage depend on the nature and severity of the disease beingtreated and the route of administration, and is within the discretion ofthe physician, and may be varied by titration of the dosage to theparticular circumstances of this invention to produce the desiredtherapeutic effect. However, it is presently contemplated thatpharmaceutical compositions containing of from about 0.01 to about 500mg of active ingredient per individual dose, preferably of from about0.1 to about 100 mg, most preferred of from about 1 to about 10 mg, aresuitable for therapeutic treatments.

The active ingredient may be administered in one or several doses perday. A satisfactory result can, in certain instances, be obtained at adosage as low as 0.01 μg/kg i.v. and 0.1 μg/kg p.o. The upper limit ofthe dosage range is presently considered to be about 10 mg/kg i.v. and100 mg/kg p.o. Preferred ranges are from about 0.1 μg/kg to about 10mg/kg/day i.v., and from about 1 μg/kg to about 100 mg/kg/day p.o.

Any possible combination of two or more of the embodiments describedherein is comprised within the scope of the present invention.

The following example will illustrate the invention further, however, itis not to be construed as limiting.

EXAMPLES Example 1

In vitro Inhibition of Anti-IgE Induced Basophil Histamine Release

The principle: By this method the ability of a test compound to inhibitanti-IgE induced basophil histamine release is measured.

Test compound: The test compound is dissolved in DMSO (stock solution:100 mM). Three concentration levels of test compound are used (endconcentrations: 30, 10, and 3 μM).

Blood samples: Heparinized whole blood is obtained from healthy nonallegic blood donors.

Method: Heparinized whole blood is washed and the plasma substitutedwith a Pipes buffer containing physiologically concentrations of NaCland KCl.

The washed whole blood is pre-incubated with the compound (aboveconcentrations) in 15 min at 37° C., Anti-IgE is added (threeconcentration levels of Anti-IgE (100, 30 and 10 U/ml), and the samplesare incubated 60 min at 37° C.

The amount of released histamine is measured using the glass-fiber basedmethod (LHRT) (HR-Test Kit from RefLab, Copenhagen, Denmark).

% inhibition is calculated as follows:$\frac{{histamine}\quad{release}\quad{when}\quad{test}\quad{compound}\quad{is}\quad{present}}{{histamine}\quad{release}{\quad\quad}{when}\quad{test}\quad{compound}\quad{is}\quad{not}\quad{present}} \times 100\%$

1. The use of a compound of the general formula IA-(X)_(p)—(Y)_(q)-(Z)_(r)-B   (I) wherein A represents a first ringstructure selected from aryl or heteroaryl; which first ring structureis optionally substituted with one or more substituents independentlyselected from the group consisting of: halogen, hydroxy, amino, oxy,cyano, nitro, trifluoromethyl, trifluoromethoxy, trifluorothiomethoxyalkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, alkoxy, aryl,arylalkyl, aryloxy, arylcarboxy, heteroaryl, —N(R²)-aryl, a 5- or6-membered monocyclic heterocyclic group, —CO₂R₂, —COR¹, -alkyl-CO₂R¹,-alkyl-COR¹, —N(R²)₂, -alkyl-N(R²)₂, —CO₂N(R¹)₂, —NHCOR¹, —CON(R¹)₂,—NHSO₂R¹, —CONHSO₂R¹, —SO₂N(R¹)₂, and —SO₂OR¹; wherein each of thealkyl, alkoxy, and cycloalkyl is optionally substituted with one or moresubstitutents independently selected from the group consisting of:halogen, hydroxy, amino, cyano, nitro, trifluoromethyl,trifluoromethoxy, trifluorothiomethoxy alkyl, cycloalkyl,cycloalkylalkyl, alkenyl, and alkynyl; each of the aryl, heteroaryl, and5- or 6-membered monocyclic heterocyclic group is optionally substitutedwith one or more one or more substitutents independently selected fromthe group consisting of: halogen, hydroxy, amino, cyano, nitro,trifluoromethyl, trifluoromethoxy, trifluorothiomethoxy alkyl,cycloalkyl, cycloalkylalkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl,—CO₂R³, —COR³, —N(R⁴)₂, -alkyl-N(R⁴)₂, —CON(R³)₂, —NHCOR³, —CON(R³)₂,—NHSO₂R³, —SO₂N(R³)₂, and —SO₂OR³; each of R¹ and R³ independently isselected from the group consisting of: hydrogen, alkyl, cycloalkyl,cycloalkylalkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, and a5-8 membered ring optionally containing double bonds and optionallycontaining one or two heteroatoms, which heteroatoms can be substitutedwith alkyl or acyl; or (R¹)₂ or (R³)₂ independently together with theheteroatom to which it is connected represents a 5-8 membered ringoptionally containing double bonds and optionally containing anotherheteroatom, which heteroatom can be substituted with alkyl or acyl; eachof R² and R⁴ independently is hydrogen or alkyl; B represents a secondring structure selected from aryl or heteroaryl; which second ringstructure is substituted with one or more acidic functional group havinga pKa value below 8, or a group which is convertible in vivo to such agroup, or a bioisostere thereof; and which second ring structure isfurthermore optionally substituted with one or more substituentsindependently selected from the group consisting of: halogen, hydroxy,amino, oxy, cyano, nitro, trifluoromethyl, trifluoromethoxy,trifluorothiomethoxy alkyl, cycloalkyl, cycloalkylalkyl, alkenyl,alkynyl, alkoxy, aryl, arylalkyl, aryloxy, arylcarboxy, heteroaryl,—N(R⁶)-aryl, a 5- or 6-membered monocyclic heterocyclic group, —CO₂R⁵,—COR⁵, -alkyl-CO₂R⁵, -alkyl-COR⁵, —N(R⁶)₂, -alkyl-N(R⁵)₂, —CON(R⁵)₂,—NHCOR⁵, —CON(R⁵)₂, —NHSO₂R⁵, —CONHSO₂R⁵, —SO₂N(R⁵)₂, and —SO₂OR⁵;wherein each of the alkyl, alkoxy, and cycloalkyl is optionallysubstituted with one or more substitutents independently selected fromthe group consisting of: halogen, hydroxy, amino, cyano, nitro,trifluoromethyl, trifluoromethoxy, trifluorothiomethoxy alkyl,cycloalkyl, cycloalkylalkyl, alkenyl, and alkynyl; each of the aryl,heteroaryl, and 5- or 6-membered monocyclic heterocyclic group isoptionally substituted with one or more one or more substitutentsindependently selected from the group consisting of: halogen, hydroxy,amino, cyano, nitro, trifluoromethyl, trifluoromethoxy,trifluorothiomethoxy alkyl, cycloalkyl, cycloalkylalkyl, alkenyl,alkynyl, alkoxy, aryl, heteroaryl, —CO₂R⁷, —COR⁷, —N(R⁸)₂,-alkyl-N(R⁸)₂, —CO₂N(R⁷)₂, —NHCOR⁷, —CON(R⁷)₂, —NHSO₂R⁷, —SO₂N(R⁷)₂, and—SO₂OR⁷; each of R⁵ and R⁷ independently is selected from the groupconsisting of: hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, alkenyl,alkynyl, aryl, arylalkyl, heteroaryl, and a 5-8 membered ring optionallycontaining double bonds and optionally containing one or twoheteroatoms, which heteroatoms can be substituted by alkyl or acyl; or(R⁵)₂ or (R⁷)₂ independently together with the heteroatom to which it isconnected represents a 5-8 membered ring optionally containing doublebonds and optionally containing another heteroatom, which heteroatom canbe substituted by alkyl or acyl; each of R⁶ and R⁸ independently ishydrogen or alkyl; X, Y, and Z are independently selected from the groupconsisting of: —CO—, —CS—, —SO₂—, —C(═NR⁹)—, —NR¹⁰—, —(CH₂)_(s)—, —O—,—CH₂—NH—, —SO₂—NH—, —CH═CH—, —C≡C—, and —N═CH—; wherein s is 1, 2, or 3;R⁹ is hydrogen, alkyl, or cyano; R¹⁰ is hydrogen or alkyl; p, q, and rindependently are 0 or 1; the sum p+q+r is 1, 2, or 3; or—(X)_(p)—(Y)_(q)-(Z)_(r)- represents

wherein Q¹ and Q² independently represent O or S; R¹¹ and R¹²independently are hydrogen or alkyl; or a pharmaceutically acceptablesalt or a prodrug thereof for the manufacture of a medicament for thetreatment, prevention or alleviation of a disorder or disease of asubject, which disorder or disease is responsive to modulation of themast cell or basophil activity of such a subject.
 2. The use accordingto claim 1, wherein the acidic functional group having a pKa below 8, ora group which is convertible in vivo to such a group is selected fromthe group consisting of: —COOH, —CH₂CO₂R¹³, —CON(R¹³)₂, tetrazolyl,methyltetrazolyl, 3-oxo-1,2-dihydro-1,2,4-triazolyl,2-oxo-3H-1,3,4-oxadiazolyl, 3-oxo-1,2-dihydro-1,2,4-triazolyl,4-hydro-1,2,4-triazolyl, —NHSO₂R¹³, —CO₂R¹³, —CO₂N(R¹³)₂, —SO₂OR¹³,—SO₂N(R³)₂, —CONHOH, —CONHNH₂, —CONHSO₂R¹³, —CONHSO₂OR¹³, —PO(OR¹³)₂,and —SO₂OR¹³; wherein each of R¹³ independently is selected from thegroup consisting of: hydrogen, alkyl, cycloalkyl, cycloalkylalkyl,alkenyl, alkynyl, aryl, aralkyl, and heteroaryl; or R¹³ comprises a 5-8membered ring optionally containing double bonds and optionallycontaining one or two heteroatoms, which heteroatoms can be substitutedby alkyl or acyl; or (R¹³)₂ together with the heteroatom to which it isconnected represents a 5-8 membered ring optionally containing doublebonds and optionally containing another heteroatom, which heteroatomscan be substituted by alkyl or acyl; and the bioisostere thereof is twoneighbouring fluoro.
 3. The use according to claims 1 or 2, wherein thefirst ring structure is optionally substituted with one or moresubstituents independently selected from the group consisting of:trifluoromethyl, halogen, alkyl, alkoxy, nitro, —COR¹, —COOH, —CH₂CO₂R¹,—CON(R¹)₂, —NHSO₂R¹, —NHCOR¹, —CO₂R¹, —CO₂N(R¹)₂, —SO₂N(R¹)₂,—CONHSO₂R¹, —SO₂OR¹, and aryl; wherein the aryl optionally issubstituted with one or more substituents selected from the group: —NO₂,—NHCOR³, —CO₂R³, —CON(R³)₂, —NHSO₂R³, and —SO₂N(R³)₂; wherein R¹ and R³are defined as above.
 4. The use according to any one of the claims 1-3wherein the second ring structure is substituted with one or more acidicfunctional group having a pKa value below 8, or a group that isconvertible in vivo to such a group, or a bioisostere thereof; and whichsecond ring structure is furthermore optionally substituted with one ormore substituents independently selected from the group consisting of:alkyl, nitro, amino, alkylamino, CO₂R⁹, CF₃, alkyl, halogen, hydroxy,alkoxy, —NHCOR⁵, —N(R⁵)₂, —CON(R⁵)₂, and aryl, wherein the aryl isoptionally substituted with one or more substituents independentlyselected from the group consisting of: —NO₂, —CON(R⁷)₂, —NHCOR⁷,—SO₂N(R⁷)₂, and —CO₂R⁷; wherein R⁵ and R⁷ are defined as above.
 5. Theuse according to any one of the claims 1-4, wherein the first ringstructure is phenyl; the second ring structure is phenyl; and—(X)_(p)—(Y)_(q)-(Z)_(r)- represents —NH—CO—NH—.
 6. The use according toany one of the claims 1-5, wherein the disorder or disease that isresponsive to modulation of the mast cell or basophil activity is adisorder or disease that is responsive to modulation of mast cell orbasophil production or secretion of histamine.
 7. The use according toany one of the claims 1-5, wherein the disorder or disease that isresponsive to modulation of the mast cell or basophil activity isallergic bronchopulmonary aspergillosis (ABPA), allergic rhinitis,allergic skin disease, allergic skin reaction, drug induced allergicskin reaction, anaphylaxis, asthma, atherosclerosis, atopic dermatitis(AD), bronchial asthma, cancer, chronic obstructive pulmonary disease(COPD), Chrohn's disease, contact dermatitis, dilated cardiomyopathy,fatal asthma, graft rejection, hypersensitivity pneumonitis, ischemichearth disease, pulmonary fibrosis, rheumatoid arthritis, systemicsclerosis, urticaria, or uveoretinitis.
 8. The use according to claim 7,wherein the disorder or disease that is responsive to modulation of themast cell or basophil activity is allergic bronchopulmonaryaspergillosis (ABPA), allergic rhinitis, allergic skin disease, allergicskin reaction, drug induced allergic skin reaction, asthma, bronchialasthma, fatal asthma and chronic obstructive pulmonary disease (COPD).9. The use according to any one of the claims 1-8 wherein the compoundis selected from 3-Trifluoromethylphenyl-N′-2-carboxyphenyl ureaN-3-Trifluoromethylphenyl-N′-3-carboxyphenyl urea;N-(2-Methoxy-5-chlorophenyl)-N′-3-carboxyphenyl urea;N-3-Trifluoromethylphenyl-N′-(2-carboxy-5-nitrophenyl) urea;N-3-Trifluoromethylphenyl-N′-(2-carboxy-4-methylphenyl) urea;N-3-Trifluoromethylphenyl-N′-(4-bromo-2-carboxyphenyl) urea;N-3-Trifluoromethylphenyl-N′-3-carbamoylphenyl urea;N-3-Trifluoromethylphenyl-N′-3-sulfamoylphenyl urea;N-3-Trifluoromethylphenyl-N′-(5-chloro-2-phenylsulfonamidocarbonylphenyl)urea; N-3-Trifluoromethylphenyl-N′-2-methylsulfonamidocarbonylphenylurea; N-3-Trifluoromethylphenyl-N′-(6-methyl-2-carboxyphenyl) urea;N-3-Trifluoromethylphenyl-N′-(3-methyl-2-carboxyphenyl) urea;N-3-Trifluoromethylphenyl-N′-(4-hydroxy-2-carboxyphenyl) urea;N-4-Nitrophenyl-N′-2-carboxyphenyl urea;N-3-Trifluoromethylphenyl-N′-2-carboxymethylphenyl urea;N-3-Trifluoromethylphenyl-N′-2-sulfophenyl urea;N-3-Trifluoromethylphenyl-N′-2-carboxyphenyl thiourea;N-3-Trifluoromethylphenyl-N′-(2-carboxy-5-trifluoromethylphenyl) urea;N-3-Trifluoromethylphenyl-N′-(4,5-dimethoxy-2-carboxyphenyl) urea;N-3-Carboxyphenyl-N′-(2-hydroxy-5-chlorophenyl) urea;N-3-Carbamoylphenyl-N′-(2-hydroxy-5-chlorophenyl) urea;N-3-Trifluoromethylphenyl-N′-(2-hydroxy-4-nitro-5-carboxyphenyl) urea;N-3-Trifluoromethylphenyl-N′-(4-carboxy-5-chloro-2-hydroxyphenyl) urea;N-3-Trifluoromethylphenyl-N′-2-amino-5-chlorophenyl) urea;N-3-Trifluoromethylphenyl-N′-(5-chloro-2-methanesulfonylaminophenyl)urea; N-3-Trifluoromethylphenyl-N′-2-carboxyphenyl urea isopropyl ester;N-3-Trifluoromethylphenyl-N′-2-carboxyphenyl urea methyl ester;N-3-Trifluoromethylphenyl-N′-2-hydrazinocarbonylphenyl urea;N-3-Trifluoromethylphenyl-N′-2-hydroxylaminocarbonylphenyl urea;2-(3′-Trifluoromethylbenzylcarboxamido)benzoic acid;N-3-Trifluoromethylphenyl-N′-4-carboxyphenyl urea;N-3-Trifluoromethylphenyl-N′-(2-carboxy-4-nitrophenyl) urea;N-3-Trifluoromethylphenyl-N′-2-carboxynapht-3-yl urea;N-3-Trifluoromethylphenyl-N′-(4-methoxy-2-carboxyphenyl) urea;N-3-Methoxyphenyl-N′-2-carboxyphenyl urea;N-4-Bromophenyl-N′-2-carboxyphenyl urea;N-3-Nitrophenyl-N′-2-carboxyphenyl urea;N-2-Methoxyphenyl-N′-2-carboxyphenyl urea;N-4-Methoxyphenyl-N′-2-carboxyphenyl urea;N-1-Naphthyl-N′-2-carboxyphenyl urea;N-2-Trifluoromethylphenyl-N′-2-carboxyphenyl urea;N-4-Methylphenylsulfonyl-N′-2-carboxyphenyl urea;N-3-Trifluoromethylphenyl-N′-(2-ethyloxycarbonylphenyl)-1,2-diaminoethane;N-(3-Trifluoromethyl)phenyl-N′-(2-carboxy)phenylsulfamide;N-3-Trifluoromethylbenzyl-N′-2-carboxyphenyl urea;N-(3-Trifluoromethyl-4-phenylphenyl)-N′-2-carboxyphenyl urea;2-(3′-Trifluoromethylphenyloxycarbonylamino)benzoic acid;N-3-Trifluoromethylphenyl-N′-(5-chloro-2-aminophenyl) urea;N-3-Trifluoromethylphenyl-N′-[4-nitro-2-(1-H-tetrazol-5-yl)phenyl] urea;N-3-Trifluoromethylphenyl-N′-[4-(2-naphthyl)-2-(1-H-tetrazol-5-yl)phenyl]urea;N-3-Trifluoromethylphenyl-N′-[4-(3-pyridyl)-2-(1-H-tetrazol-5-yl)phenyl]urea;N-3-Trifluoromethylphenyl-N′-[4-(1-naphthyl)-2-(1-H-tetrazol-5-yl)phenyl]urea;N-3-Trifluoromethylphenyl-N′-[4-(4-trifluoromethylphenyl)-2-(1-H-tetrazol-5-yl)phenyl]urea;N-3-Trifluoromethylphenyl-N′-[4-(3-furyl-2-(1-H-tetrazol-5-yl)phenyl]urea;N-3-Trifluoromethylphenyl-N′-[4-(3-thienyl)2-(1-H-tetrazol-5-yl)phenyl]urea;N-3-Trifluoromethylphenyl-N′-[4-(3-nitrophenyl)-2-(1-H-tetrazol-5-yl)phenyl]urea;N-3-Trifluoromethylphenyl-N′-[4-(4-ethoxycarbonylphenyl)-2-(1-H-tetrazol-5-yl)phenyl]urea;N-3-Trifluoromethylphenyl-N′-[4-(4-dimethylaminocarbonylphenyl)-2-(1-H-tetrazol-5-yl)phenyl]urea;N-3-Trifluoromethylphenyl-N′-[4-(4-aminocarbonylphenyl)-2-(1-H-tetrazol-5-yl)phenyl]urea;N-3-Trifluoromethylphenyl-N′-2-(4-hydroxy-1,2,4-triazol-3-yl)phenylurea;N-3-Trifluoromethylphenyl-N′-2-(3-oxo-1,2-dihydro-1,2,4-triazol-1-yl)phenylurea;N-3-Trifluoromethylphenyl-N′-2-(2-oxo-3H-1,3,4-oxadiazol-5-yl)phenylurea;N-3-Trifluoromethylphenyl-N′-[5-phenyl-2-(3-oxo-1,2-dihydro-1,2,4-triazol-1-yl)phenyl]urea; N-3-Trifluoromethylphenyl-N′-[4-amino-2-(1-H-tetrazol-5-yl)phenyl]urea;N-3-Trifluoromethylphenyl-N′-[4-acetylamino-2-(1-H-tetrazol-5-yl)phenyl]urea;N-3-Trifluoromethylphenyl-N′-[4-benzoylamino-2-(1-H-tetrazol-5-yl)phenyl]urea;N-3-Trifluoromethylphenyl-N′-[4-(4-carboxyphenyl)-2-(1-H-tetrazol-5-yl)phenyl]urea;N-3-Trifluoromethylphenyl-N′-[4-(4-anilinocarbonylphenyl)-2-(1-H-tetrazol-5-yl)phenyl]urea; N-4-Biphenylyl-N′-2-1-H-tetrazol-5-yl)phenyl urea;N-3-Biphenylyl-N′-2-(1-H-tetrazol-5-yl)phenyl urea;N-5-Indanyl-N′-2-(1-H-tetrazol-5-yl)phenyl urea;N-3-Bromophenyl-N′-[4-bromo-2-(1-H-tetrazol-5-yl)phenyl] urea;N-3-Acetylphenyl-N′-2-(1-H-tetrazol-5-yl)phenyl urea;N-3-Biphenylyl-N′-[4-bromo-2-(1-H-tetrazol-5-yl)phenyl] urea;N-3-(3-Pyridyl)phenyl-N′-[4-bromo-2-(1-H-tetrazol-5-yl)phenyl] urea;N-3-Trifluoromethylphenyl-N′-[4-bromo-2-(1-H-tetrazol-5-yl)phenyl urea];N-3-Trifluoromethylphenyl-N′-2-(1-H-tetrazol-5-yl)phenyl urea;N-3-Trifluoromethylphenyl-N′-2-(1-H-tetrazol-5-yl)phenyl thiourea;N-3-Trifluoromethylphenyl-N′-[4-phenyl-2-(1-H-tetrazol-5-yl)phenyl]urea; N-4-Trifluoromethylphenyl-N′-2-(1-H-tetrazol-5-yl)phenyl urea;N-3-Chlorophenyl-N′-2-(1-H-tetrazol-5-yl)phenyl urea;N-Phenyl-N′-2-(1-H-tetrazol-5-yl)phenyl urea;N-3-Bromophenyl-N′-[4-bromo-2-(1-H-tetrazol-5-yl)phenyl] urea;3-[4-Bromo-2-(1-H-tetrazol-5-yl)-phenylamino]-4-(3-trifluoromethyl-phenylamino)-3-cyclobuten-1,2-dione;3-(3-Bromo-phenylamino)-[4-bromo-(1-H-tetrazol-5-yl)-phenylamino]-3-cyclobuten-1,2-dione;3-(3-Bromo-phenylamino)-4-[4′-(N,N-dimethylsulfonamide)-2-(1-H-tetrazol-5-yl)-biphenylamino]-3-cyclobuten-1,2-dione;3-(3-Bromo-phenylamino)-4-[2-(1-H-tetrazol-5-yl)-biphenylamino]-3-cyclobuten-1,2-dione;N-Phenyl-N′-(2-carboxyphenyl) urea;N-3-Trifluoromethylphenyl-N′-(2-carboxyphenyl)-N′-methyl urea;N-3-Trifluoromethylphenyl-N′-(4-bromo-2-carboxyphenyl) urea;N-3-Trifluoromethylphenyl-N′-(2-carboxy-4-chlorophenyl) urea;N-3-Trifluoromethylphenyl-N′-(2-carboxy-4-fluorophenyl) urea;N-3-Trifluoromethylphenyl-N′-(5-bromo-2-carboxyphenyl) urea;N-3-Trifluoromethylphenyl-N′-(2-carboxy-5-chlorophenyl) urea;N-3-Bromophenyl-N′-[2-(1-H-tetrazol-5-yl)-4-biphenyl] urea;N-3-Trifluoromethylphenyl-N′-[4′-(N,N-dimethylsulfamoyl)-2-(1-H-tetrazol-5-yl)-4-biphenyl]urea;N-3-Bromophenyl-N′-[4′-(N,N-dimethylsulfamoyl)-2-(1-H-tetrazol-5-yl)-4-biphenyl]urea;N-3-Bromophenyl-N′-[4′-(N,N-dimethylcarbamoyl)-2-(1-H-tetrazol-5-yl)-4-biphenyl]urea; N-3-Trifluoromethylphenyl-N′-[4-amino-2-(1-H-tetrazol-5-yl)phenyl]urea;N-3-Trifluoromethylphenyl-N′-[4-acetylamino-2-(1-H-tetrazol-5-yl)phenyl]urea;N-3-Trifluoromethylphenyl-N′-[4′-carbamoyl-2-(1-H-tetrazol-5-yl)-4-biphenyl]urea;N-3-Trifluoromethylphenyl-N-[4′-(N,N-dimethylcarbamoyl)-2-(1-H-tetrazol-5-yl)-4-biphenyl]urea;N-3-Trifluoromethylphenyl-N′-[4′-carboxy-2-(1-H-tetrazol-5-yl)-4-biphenyl]urea; 1-(3-Trifluoromethylphenyl)-3-(2-carboxyphenyl)-2-imidazolidone;N-3-Trifluoromethylphenyl-N′-[4-(4-benzoylcarbonylphenyl)-2-(1-H-tetrazol-5-yl)phenyl]urea; N-4-Biphenylyl-N′-2-(1-H-tetrazol-5-yl)phenyl urea;N-3-Bromophenyl-N′-[3′-nitro-2-(1-H-tetrazol-5-yl)biphenyl] urea;N-3-Bromophenyl-N′-[4′-(sulfoamido-N-methylpiperaziniumchloride)-2-(1-H-tetrazol-5-yl)-4-biphenyl] urea;N-3-Bromophenyl-N-[4′-(carbamoyl-N-methylpiperazine)-2-(1-H-tetrazol-5-yl)-4-biphenyl]urea; N-3,5-Dichlorophenyl-N′-[4-bromo-2-(1-H-tetrazol-5-yl)phenyl]urea; N-4-Trifluoromethylphenyl-N′-[4-bromo-2-(1-H-tetrazol-5-yl)phenyl]urea; N-4-Bromophenyl-N′-[4-bromo-2-(1-H-tetrazol-5-yl)phenyl] urea;N-3-Methoxyphenyl-N′-[4-bromo-2-(1-H-tetrazol-5-yl)phenyl] urea;N-3-Chlorophenyl)-N′-[4-bromo-2-(1-H-tetrazol-5-yl)phenyl] urea;N-3-Methylphenyl-N-[4-bromo-2-(1-H-tetrazol-5-yl)phenyl] urea;N-3,4-Dichlorophenyl-N′-[4-bromo-2-(1-H-tetrazol-5-yl)phenyl] urea;N-2-Naphthyl-N-[4-bromo-2-(1-H-tetrazol-5-yl)phenyl] urea;N-(4-Methyl-3-nitrophenyl)-N′-[4-bromo-2-(1-H-tetrazol-5-yl)phenyl]urea;N-(2-Chloro-4-trifluoromethylphenyl)-N′-[4-bromo-2-(1-H-tetrazol-5-yl)phenyl]urea;N-3,5-Di(trifluoromethyl)phenyl-N′-[4-bromo-2-(1-H-tetrazol-5-yl)phenyl]urea; N-3,5-Dimethylphenyl-N-[4-bromo-2-(1-H-tetrazol-5-yl)phenyl] urea;N-4-Ethoxyphenyl-N′-[4-bromo-2-(1-H-tetrazol-5-yl)phenyl] urea;N-4-Methoxyphenyl-N′-[4-bromo-2-(1-H-tetrazol-5-yl)phenyl] urea;N-2-Trifluoromethylphenyl-N′-[4-bromo-2-(I-H-tetrazol-5-yl)phenyl] urea;N-2-Bromophenyl-N′-[4-bromo-2-(1-H-tetrazol-5-yl)phenyl] urea;N-2-Chlorophenyl-N′-[4-bromo-2-(1-H-tetrazol-5-yl)phenyl] urea;N-2-Fluorophenyl-N′-[4-bromo-2-(1-H-tetrazol-5-yl)phenyl] urea;N-(4-Chloro-3-trifluoromethylphenyl)-N′-[4-bromo-2-(1-H-tetrazol-5-yl)phenyl]urea; N-3-Bromophenyl-N′-2,3-difluorophenyl urea;N-2-Methylphenyl-N-[4-bromo-2-(1-H-tetrazol-5-yl)phenyl] urea;N-2-Ethylphenyl-N′-[4-bromo-2-(1-H-tetrazol-5-yl)phenyl] urea;N-4-Methylphenyl-N-[4-bromo-2-(1-H-tetrazol-5-yl)phenyl] urea;N-2-Nitrophenyl-N′-[4-bromo-2-(1-H-tetrazol-5-yl)phenyl] urea;N-3-Fluorophenyl-N′-[4-bromo-2-(1-H-tetrazol-yl)phenyl] urea;N-4-(2-Propyl)phenyl-N-[4-bromo-2-(1-H-tetrazol-5yl)phenyl] urea;N-3-Nitrophenyl-N-[4-bromo-2-(1-H-tetrazol-5-yl)phenyl] urea;N-3-Acetylphenyl-N′-[4-bromo-2-(1-H-tetrazol-5-yl)phenyl] urea;N-4-Nitrophenyl-N′-[4-bromo-2-(1-H-tetrazol-5-yl)phenyl] urea;N-3-Trifluoromethylphenyl-N′-2-carboxyphenyl urea;N-Phenyl-N-2-carboxyphenyl urea;N-3-Trifluoromethylphenyl-N′-2-carboxyphenyl-N-methyl urea;N-3-Trifluoromethylphenyl-N′-[4′-(N-phenylcarbamoyl)-2-(1-H-tetrazol-5-yl)-4-biphenyl]urea; N-(2-Indan)-N′-2-(1-H-tetrazol-5-yl)phenyl urea;N-(4-Biphenyl)-N′-2-(1-H-tetrazol-5-yl)phenyl urea;N-(3-Biphenyl)-N′-2-(1-H-tetrazol-5-yl)phenyl urea;N-(3-Acetylphenyl)-N′-2-(1-H-tetrazol-5-yl)phenyl urea;N-3-Trifluoromethylphenyl-N′-[2-(1-methyltetrazol-5-yl)-4-biphenyl]urea; N-(3-Biphenyl)-N′-[4-bromo-2-(1-H-tetrazol-5-yl)phenyl] urea;N-3-(3-Pyridyl)phenyl-N′-[4bromo-2-(1-H-tetrazol-5-yl)phenyl] ureahydrochloride; N-3-Bromophenyl-N′-[4-bromo-2-(1-H-tetrazol-5-yl)phenyl]urea; 1-3-Trifluoromethylphenyl)-3-(2-carboxyphenyl)-2-imidazolidone;N-(4-Biphenylyl)-N′-2-(1-H-tetrazol-5-yl)phenyl urea;N-(3-Biphenylyl)-N′-2-(1-H-tetrazol-5-yl)phenyl urea;N-(5-Indanyl)-N′-2-(1-H-tetrazol-5-yl)phenyl urea;N-(2-Chloro-5-trifluoromethylphenyl)-N′-[4-bromo-2-(1-H-tetrazol-5-yl)phenyl]urea; N-4-Bromophenyl-N′-(2-carboxy-5-chlorophenyl) urea;N-4-Trifluoromethylphenyl-N′-(2-carboxy-5-chlorophenyl) urea;N-3-Bromophenyl-N′-(2-carboxy-5-chlorophenyl) urea;N-3-Nitrophenyl-N′-(2-carboxy-5-chlorophenyl) urea;N-3-Methoxyphenyl-N′-(2-carboxy-5-chlorophenyl) urea;N-(4-Chloro-3-trifluoromethylphenyl)-N′-(2-carboxy-5-chlorophenyl) urea;N-3-Fluorophenyl-N′-(2-carboxy-5-chlorophenyl) urea;N-3-Fluorophenyl-N′-(2-carboxy-5-fluorophenyl) urea;N-3-Trifluoromethylphenyl-N′-(2-carboxy-4,5-difluorophenyl) urea;N-3,5-Bis(trifluoromethyl)phenyl)-N′-(2-carboxy-5-chlorophenyl) urea;N-3-Trifluoromethylphenyl-N′-(2-carboxy-5-nitrophenyl) urea;N-3,4-Dichlorophenyl-N′-[5-methyl-2-(1-H-tetrazol-5-yl)phenyl] urea;N-3,4-Dichlorophenyl-N′-[5chloro-2-(1-H-tetrazol-5-yl)phenyl] urea;N-3-Trifluoromethylphenyl-N′-(3-carboxy-4-chlorophenyl) urea;N-(3-Chloro-4-hydroxyphenyl)-N′-[4-bromo-2-(1-H-tetrazol-5-yl)phenyl]urea; N-2,3,4-Trifluorophenyl-N′-[4-bromo-2-(1-H-tetrazol-5-yl)phenyl]urea; N-3,4-Difluorophenyl-N′-[4-bromo-2-(1-H-tetrazol-5yl)phenyl] urea;N-3-Chlorophenyl-N′-2,3-difluorophenyl urea;N-(3-Chloro-4-fluorophenyl)-N′-[4-bromo-2-(1-H-tetrazol-5-yl)phenyl]urea; N-2,4,5-Trifluorophenyl-N′-[4-bromo-2-(1-H-tetrazol-5-yl)phenyl]urea; N-3,5-Bis(trifluoromethyl)phenyl)-N′-2-(1-H-tetrazol-5-yl)phenylurea;N-3,5-Bis(trifluoromethyl)phenyl)-N′-[2,4-dibromo-6-(1-H-tetrazol-5-yl)phenyl]urea;N-(4-Fluoro-3-trifluoromethylphenyl)-N′-[4-bromo-2-(1-H-tetrazol-5-yl)phenyl]urea; N-3,5-Difluorophenyl-N′-[4-bromo-2-(1-H-tetrazol-5-yl)phenyl]urea;N-3,5-Bis(trifluoromethyl)phenyl-N′-[4′-(N,N-dimethylsulfamoyl)-2-(1-H-tetrazol-5-yl)-(4-biphenyl)]urea; N-3,5-Dichlorophenyl-N′-[4′-(N,N-dimethylsulfamoyl)-2-(I-H-tetrazol-5-yl)-4-biphenyl] urea;N-2,3-Difluorophenyl-N′-3-trifluoromethylphenyl urea;N-2,3-Difluorophenyl-N′-(4-chloro-3-trifluoromethylphenyl) urea;N-3,4-Dichlorophenyl-N′-2,3-trifluorophenyl urea;N-2,3-Difluorophenyl-N′-3-trifluoromethylphenyl thiourea;N-2,3-Difluorophenyl-N′-2-fluorophenyl urea;N-2,3-Difluorophenyl-N′-3-methoxyphenyl urea;N-3,4-Dichlorophenyl-N′-2,3,4-trifluorophenyl urea;N-(4-Chloro-3-trifluoromethylphenyl)-N′-2,3,4-trifluorophenyl urea;N-3-Chlorophenyl-N′-(2-hydroxy-4-methylphenyl) urea;N-2,3-Difluorophenyl-N′-[3′-(pyridin-3-yl)phenyl] urea;N-3,5-Dichlorophenyl-N′-2,3-difluorophenyl urea;N-2,3-Difluorophenyl-N′-3-nitrophenyl urea; and pharmaceuticallyacceptable salts and prodrugs thereof.
 10. A method of treatment,prevention or alleviation of a disorder or disease of a subject, whichdisorder or disease is responsive to modulation of the mast cell orbasophil activity of such a subject, which method comprisesadministering to said subject a therapeutically effective amount of acompound of general formula I as defined in claim 1 or apharmaceutically acceptable salt or a prodrug thereof.